Our Gut Microbiota Changes as We Get Older
As we move through life, the processes that normally keep cellular damage and other genetic/cellular abnormalities in check break down. Things just don't work the way they used to. For example, aged cells don't clear out waste products as well; accumulation of these products hinders cell function. Other hallmarks like genomic instability, epigenetic alterations and cellular senescence also intersect to contribute to aging.
But there is yet another string in this intricate web: the gut microbiota.
"Aging is a complex life history trait, and it encompasses so many different aspects of physiology," said Shuo Han, Ph.D., an assistant professor of biochemistry at Duke University School of Medicine. This complexity makes unearthing connections between aging and gut microbes challenging to study. However, "over the past decade, many people have begun to study this connection using different animal model systems." She pointed to experiments in mice and African killifish models that have revealed how the fecal microbiota plays important, functional roles in regulating aspects of host aging biology (e.g., gut and neurological function).
Gut microbes have been implicated in the normal aging process, as well as conditions and syndromes common among elderly individuals, like dementia and frailty. In older age, gut microbiota diversity-considered an indicator of a "healthy" microbiome-tends to decrease. Some research shows that the microbiota of centenarians and supercentenarians (those who live to be over 100 years old) is more diverse than less healthy individuals, pointing to its potential importance in aging.
Compositionally, the microbiota in healthily aging individuals does somewhat of a flip-flop-microbes enriched in younger adult years (Bacteroides) become less dominant, whereas taxa that existed on the fringes of the community (Clostridia) become more so. This waxing and waning of taxa are not just for show; a study found that older individuals (over ~80 years) who retained dominance of Bacteroides in their guts were more likely to die over a 4-year follow-up period than those who didn't. Not all bacteria that stick around are a problem, though. Some research suggests that healthier elderly individuals tend to retain higher levels of certain bacteria tied to gut and systemic health (e.g., Akkermansia).
Determining what drives these microbial shifts is the ultimate whodunit-there are many suspects, and none of them act alone. Though some age-related microbiota changes are conserved across populations, many vary depending on geographic location and age range. Diet, medication and whether someone lives in a nursing/health care facility also matter, with the latter being associated with more chronic health conditions and enrichment in possibly pathogenic gut microbes. Physiological factors that shift with age, like slowed digestion and reduced levels of digestive enzymes, shape the microbiota as well.
How Does the Microbiota Contribute to Aging?
How exactly the microbiota plugs into the aging process is a-if not the-key question in the field. Do microbiota changes trigger features of aging, or are they a reflection of other changes going on in the body? It's probably a bit of both.
"We should think about aging-microbiome interactions as a 2-way street," Han said. "On the one hand, gut bacterial community changes as the host ages. As a result, the overall metabolism by this community changes as well. On the other hand, the gastrointestinal tract from an aging host can become more susceptible to inflammation and tissue damage at an older age, thereby no longer serving as a nourishing environment for the same gut bacterial community that was present in their youth."
Old age is characterized by an increased level of low-grade, chronic inflammation known as inflammaging. The more of this simmering inflammation someone has, the higher their risk of developing chronic health conditions and syndromes (e.g., cardiovascular disease, dementia, frailty). Loss of microbiota members who produce compounds like short chain fatty acids (SCFAs) that bolster the integrity of the gut barrier may help spur inflammaging. A robust barrier keeps microbes and molecules out of the immune-cell-rich underbelly of the gut lining and broader circulation, whereas a leaky barrier can jumpstart an inflammatory response that impacts organs throughout the body.
"We all get older by numbers, but we all develop different kind of health conditions," noted Hariom Yadav, Ph.D., an associate professor of neurosurgery and brain repair at the University of South Florida who studies leaky gut and age-related conditions, like dementia. How much microbiota-triggered inflammation an organ is exposed to-along with potentially harmful host and microbial metabolites leaching from the gut into places they don't belong-may cause it to deteriorate faster than other organs, and more quickly in some people than others. "That's the power of the microbiome" Yadav said.
Studies in mice show that transferring the microbiota of old animals into young mice promotes inflammaging, suggesting the microbiota takes an active role in the process. Conversely, transferring the microbiota of young mice into old mice can reverse or temper some of aging's metabolic and immunological effects.
Inflammation triggered by other aging-related processes may also sculpt the microbiota, selecting for bacteria (e.g., Escherichia and Klebsiella) that tend to thrive in inflamed environments characterized by altered nutrient pools and enriched oxygen levels. These microbes can further perpetuate inflammation, which then selects for more of the organisms that survive in it. Notably, treating inflammaging in mice with an antibody targeting the pro-inflammatory cytokine TNF reverses age-related microbiota changes, underscoring inflammation's role in shaping the community.
There is ultimately a lot that goes into how the microbiota looks and, as a result, how it functions, during both healthy and unhealthy aging. Scientists like Yadav are eager to make sense of all the complexity, with an eye toward using what they learn to prolong the health span of the elderly population. "We do all this fancy science in the lab, but how do we really take it to the people?" he asked. "How can we make this implemented into people's daily lives?"
Harnessing the Gut Microbiota to Promote Healthy Aging
While there is no microbial answer to eternal youth, there are efforts toward understanding if and how we can leverage the microbiota to age as healthily as possible.
Diet
Diet is a key target with potentially big payoffs. Shifts in the aged microbiota associated with poorer health have dietary roots (e.g., reduced fiber intake, which starves SCFA-producers and other health-promoting microbes). For instance, individuals aged 65-79 years old who ate a Mediterranean diet for 1 year had improved cognitive function, and lower inflammatory and frailty markers; their microbiomes were enriched in production of SCFAs. As such, boosting consumption of fiber, fermented foods and other foods with health-promoting powers as we age can help bolster health by way of the microbiota.
Supplements
Microbial supplements (e.g., pre- or probiotics) offer another possibility. Studies in preclinical models demonstrate that probiotic supplementation may be effective at modulating aging-associated changes, such as cognitive decline or reduced SCFA concentrations. Yadav's lab has shown that even dead probiotics (what he calls "postbiotics") can have anti-aging effects in mice; his team has focused specifically on a strain of Lactobacillus paracasei derived from a healthy infant gut. "[The postbiotic] has a cell wall component that promotes mucus formation," he explained. "The mucus layer becomes thick [and] gut permeability decreases. This reduces leaky gut [and] inflammation and improves cognitive function, metabolic function [and] muscle function, which are important functions that declines during aging." He and his colleagues are currently working on commercializing their postbiotic formulation.
Still, clinical evidence about the benefits of probiotics (or any other "biotics") in aging can be spotty. Han emphasized understanding how they work and their effectiveness depends on how they are administered and their formulation. "It's a mixed bag," she said. As researchers get a better handle on the specific microbiota changes that come with age, there is potential to develop targeted formulations that replace declining microbial species.
Fecal Microbiota Transplants?
But what about replacing the whole microbial kit and kaboodle? Studies in animal models suggest that fecal microbiota transplants (FMTs) from young to old mice can modulate aging outcomes. Could the same be true in humans? Clinically, FMTs have demonstrated success in combating particularly stubborn infections by the pathogen Clostridioides difficile. However, their use in the context of other health conditions/states-particularly those that are less "defined" than C. difficile infection-is largely investigative, if not speculative. Some researchers suggest that reverting the microbiota to a younger state via FMTs may not be an ideal approach. The microbiota is meant to change throughout life. Cultivating a "young" community in an older body may lead to a mismatch in what the microbiota does and can do, and what benefits the host.
The Road Ahead
"What the microbiota does and can do" is a critical focus in the aging microbiome world. When asked about the future of the field, Han pointed to identifying gut bacterial products (e.g., metabolites) and deciphering how they contribute to distinct aspects of host aging biology, such as brain and metabolic health. Most metabolites bacteria make are unknown or understudied, meaning what they do is largely a mystery.
"It's important as a next step to understand what functional roles distinct species have in conferring health benefits," she said. "One can imagine that while some bacterial species are enriched in long-lived humans, they likely are not all beneficial." Her lab is working to map the bioactive molecules produced by prevalent human gut bacterial species/strains and, using aging models like Caenorhabditis elegans and mice, determine how they impact distinct features of aging physiology.
For Yadav, understanding what microbes eat is equally as important as determining what they make. Some microbes may eat toxic metabolites that enter or are generated by the body. Without these microbes, such metabolites circulate back into our bodies and may negatively impact systemic health, he explained. Connecting the dots between which microbes are present, what they eat, what they secrete and how all of it impacts the host is necessary for figuring out how best to leverage the microbiota for optimal aging.
At the end of the day (and life), "we need to keep watching our gut and the tiny bugs living in there," Yadav said. "They [can] keep us healthy and happy as we grow older."
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